This proposal will focus on interindividual differences in susceptibility to tobacco carcinogenesis in former smokers who continue to exhibit substantially increased cancer risks after smoking cessation. We propose to conduct a casecontrol study of 400 lung cancer patients who classify themselves as former smokers (> one year cessation) at diagnosis. Controls (n = 400), matched to the cases on sex, age (+/- 5 years), ethnicity, duration of smoking cessation (+/- 6 months), and pack-year history (+/- 5 years), will be selected from a large pool of eligible controls identified from the rosters of the largest multi-specialty healthcare group practice in the Houston metropolitan area. The hypothesis being tested is that former smokers who express increased susceptibility to tobacco carcinogenesis (at any phase of carcinogenesis) are at greater risk for smoking-related cancers than are non-susceptible former smokers. We will measure susceptibility at several stages in tobacco carcinogenesis including genetic modulation of carcinogen activation and detoxification, chromosome sensitivity to tobacco mutagens, and DNA repair capacity. The specific aims are: 1. To assess tobacco mutagen sensitivity as a predictor of case status by quantifying the number and location of chromatid breaks induced by in vitro exposure to bleomycin (a radiomimetic agent) and benzo[a]pyrene diol epoxid (BPDE, an activated form of B[a]P), a tobacco carcinogen. 2. To evaluate DNA repair capacity after BPDE-induced mutagenesis by using the host cell reactivation assay (HCR in cases and controls. 3. To describe the genotypic characteristics of cases and controls by comparing the frequencies of several susceptibility markers, i.e., two cytochrome p450 (CYP) genes (CYP2D6 and CYP1A1); glutathione-S-transferase (GST) mu and theta; and the arginine-to-proline polymorphism at codon 72 of the p53 gene. The cases accrued for this study who present with early stage disease will also be eligible for enrollment in the Project 1 chemoprevention trial (Hong/Kurie). The exposure and marker data will be integrated with the clinical and prognostic data of Project 1 and the molecular genetic, proliferation marker, and receptor data derived from Projects 3 (Hittelman) and 4 (Lotan). The ability to identify former smokers with the highest risks of developing lung cancer has substantial preventive implications.